Heat shock protein 90 (HSP90) is an abundant and evolutionarily highly conserved molecular chaperone that regulates the maturation, activity and stability of a wide range of substrate proteins (clients). In eukaryotes, HSP90 is essential for survival during heat and other stresses, but it also has a central role in a vast array of signal transduction pathways in non-stressful conditions.
HSP90 exists as a dimer that undergoes ATP-dependent conformational changes during client protein maturation (known as the chaperone cycle). How the chaperone cycle is mechanistically connected to client protein folding is just beginning to be understood. The extreme conformation flexibility of HSP90 sets it apart from other chaperone systems and renders its study remarkably complex.
More than 20 known co-chaperones regulate HSP90 function in many different ways. Some co-chaperones modulate HSP90 ATPase activity and the chaperone cycle, and others seem to function as adaptors that recruit specific client proteins. Post-translational modifications of HSP90 and co-chaperones add further regulatory layers.
The best-characterized HSP90 client proteins are kinases and steroid hormone receptors. However, recent studies have uncovered numerous genes and proteins that either physically or genetically interact with HSP90. In yeast, Hsp90 is functionally linked to ∼20% of all genes. HSP90 has been implicated in RNA processing, membrane trafficking and in innate and adaptive immunity.
Despite the numerous client proteins, clear structural or sequence determinants for HSP90 binding remain largely unknown. Client protein recognition is one of the largest puzzles in the field.
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins (known as clients). Clients are enriched in signal transducers, including kinases and transcription factors. Therefore, HSP90 regulates diverse cellular functions and exerts marked effects on normal biology, disease and evolutionary processes. Recent structural and functional analyses have provided new insights on the transcriptional and biochemical regulation of HSP90 and the structural dynamics it uses to act on a diverse client repertoire. Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ellis, R. J. Protein misassembly: macromolecular crowding and molecular chaperones. Adv. Exp. Med. Biol. 594, 1–13 (2007).
Zou, Z. et al. Hyper-acidic protein fusion partners improve solubility and assist correct folding of recombinant proteins expressed in Escherichia coli. J. Biotechnol. 135, 333–339 (2008).
Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).
Hartl, F. U. & Hayer-Hartl, M. Converging concepts of protein folding in vitro and in vivo. Nature Struct. Mol. Biol. 16, 574–581 (2009).
Doyle, S. M. et al. Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity. Nature Struct. Mol. Biol. 14, 114–122 (2007).
McClellan, A. J., Tam, S., Kaganovich, D. & Frydman, J. Protein quality control: chaperones culling corrupt conformations. Nature Cell Biol. 7, 736–741 (2005).
Young, J. C., Hoogenraad, N. J. & Hartl, F. U. Molecular chaperones Hsp90 and HSP70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112, 41–50 (2003).
Retzlaff, M. et al. Hsp90 is regulated by a switch point in the C-terminal domain. EMBO Rep. 10, 1147–1153 (2009).
Hainzl, O., Lapina, M. C., Buchner, J. & Richter, K. The charged linker region is an important regulator of Hsp90 function. J. Biol. Chem. 284, 22559–22567 (2009).
Mickler, M., Hessling, M., Ratzke, C., Buchner, J. & Hugel, T. The large conformational changes of Hsp90 are only weakly coupled to ATP hydrolysis. Nature Struct. Mol. Biol. 16, 281–286 (2009).
Richter, K. et al. Conserved conformational changes in the ATPase cycle of human Hsp90. J. Biol. Chem. 283, 17757–17765 (2008).
Vaughan, C. K. et al. Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Mol. Cell 31, 886–895 (2008).
Vaughan, C. K. et al. Structure of an Hsp90-Cdc37-Cdk4 complex. Mol. Cell 23, 697–707 (2006). The first structural analysis of an HSP90–co-chaperone–client complex, paving the way for the molecular-level understanding of HSP90 specificity and function.
Krukenberg, K. A., Southworth, D. R., Street, T. O. & Agard, D. A. pH-dependent conformational changes in bacterial Hsp90 reveal a Grp94-like conformation at pH6 that is highly active in suppression of citrate synthase aggregation. J. Mol. Biol. 390, 278–291 (2009).
McClellan, A. J. et al. Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131, 121–135 (2007).
Zhao, R. et al. Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the Hsp90 chaperone. Cell 120, 715–727 (2005).
Zhao, R. & Houry, W. A. Hsp90: a chaperone for protein folding and gene regulation. Biochem. Cell Biol. 83, 703–710 (2005).
Gong, Y. et al. An atlas of chaperone–protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell. Mol. Syst. Biol. 5, 275 (2009).
Millson, S. H. et al. A two-hybrid screen of the yeast proteome for Hsp90 interactors uncovers a novel Hsp90 chaperone requirement in the activity of a stress-activated mitogen-activated protein kinase, Slt2p (Mpk1p). Eukaryot. Cell 4, 849–860 (2005).
Borkovich, K. A., Farrelly, F. W., Finkelstein, D. B., Taulien, J. & Lindquist, S. Hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures. Mol. Cell. Biol. 9, 3919–3930 (1989).
Pratt, W. B. & Toft, D. O. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306–360 (1997).
Akner, G., Mossberg, K., Sundqvist, K. G., Gustafsson, J. A. & Wikstrom, A. C. Evidence for reversible, non-microtubule and non-microfilament-dependent nuclear translocation of hsp90 after heat shock in human fibroblasts. Eur. J. Cell Biol. 58, 356–364 (1992).
Biggiogera, M. et al. Localization of heat shock proteins in mouse male germ cells: an immunoelectron microscopical study. Exp. Cell Res. 229, 77–85 (1996).
Langer, T., Rosmus, S. & Fasold, H. Intracellular localization of the 90 kDA heat shock protein (HSP90α) determined by expression of a EGFP-HSP90α-fusion protein in unstressed and heat stressed 3T3 cells. Cell Biol. Int. 27, 47–52 (2003).
Tsutsumi, S. & Neckers, L. Extracellular heat shock protein 90: a role for a molecular chaperone in cell motility and cancer metastasis. Cancer Sci. 98, 1536–1539 (2007).
Eustace, B. K. et al. Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness. Nature Cell Biol. 6, 507–514 (2004). The authors show an intriguing role for extracellular HSP90α in the regulation of matrix metalloproteinase 2 activity, and that extracellular inhibition of HSP90 reduces cell invasiveness, suggesting a new therapeutic strategy.
Kang, B. H. et al. Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131, 257–270 (2007). The authors show that a fraction of HSP90 is localized to mitochondria in tumour cells but not in normal cells. Similarly, the mitochondrial HSP90, TRAP1, is much more abundant in tumour cells than in normal tissues. Strikingly, inhibition of HSP90 and TRAP1 function in mitochondria leads to tumour cell-specific apoptosis.
Zhou, Y. N., Kusukawa, N., Erickson, J. W., Gross, C. A. & Yura, T. Isolation and characterization of Escherichia coli mutants that lack the heat shock σ factor σ32. J. Bacteriol. 170, 3640–3649 (1988).
Jenkins, D. E., Auger, E. A. & Matin, A. Role of RpoH, a heat shock regulator protein, in Escherichia coli carbon starvation protein synthesis and survival. J. Bacteriol. 173, 1992–1996 (1991).
Vanaporn, M., Vattanaviboon, P., Thongboonkerd, V. & Korbsrisate, S. The rpoE operon regulates heat stress response in Burkholderia pseudomallei. FEMS Microbiol Lett. 284, 191–196 (2008).
Whitesell, L. & Lindquist, S. Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opin. Ther. Targets. 13, 469–478 (2009).
Sorger, P. K. & Pelham, H. R. Purification and characterization of a heat-shock element binding protein from yeast. EMBO J. 6, 3035–3041 (1987).
Nadeau, K., Das, A. & Walsh, C. T. Hsp90 chaperonins possess ATPase activity and bind heat shock transcription factors and peptidyl prolyl isomerases. J. Biol. Chem. 268, 1479–1487 (1993).
Ammirante, M. et al. The activity of hsp90α promoter is regulated by NF-κB transcription factors. Oncogene 27, 1175–1178 (2008).
Stephanou, A. et al. Interleukin 6 activates heat-shock protein 90β gene expression. Biochem. J. 321, 103–106 (1997).
Ripley, B. J., Stephanou, A., Isenberg, D. A. & Latchman, D. S. Interleukin-10 activates heat-shock protein 90β gene expression. Immunology 97, 226–231 (1999).
Sekimoto, T. et al. The molecular chaperone Hsp90 regulates accumulation of DNA polymerase ɛ at replication stalling sites in UV-irradiated cells. Mol. Cell 37, 79–89 (2010).
Shiau, A. K., Harris, S. F., Southworth, D. R. & Agard, D. A. Structural analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements. Cell 127, 329–340 (2006).
Ali, M. M. et al. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440, 1013–1017 (2006). This comprehensive crystal structure of yeast Hsp90 in complex with the co-chaperone p23 provides a glimpse into a closed structure of the full-length Hsp90 dimer.
Dollins, D. E., Warren, J. J., Immormino, R. M. & Gewirth, D. T. Structures of GRP94-nucleotide complexes reveal mechanistic differences between the Hsp90 chaperones. Mol. Cell 28, 41–56 (2007).
Pearl, L. H. & Prodromou, C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu. Rev. Biochem. 75, 271–294 (2006).
Prodromou, C., Roe, S. M., Piper, P. W. & Pearl, L. H. A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone. Nature Struct. Biol. 4, 477–482 (1997).
Stebbins, C. E. et al. Crystal structure of an Hsp90–geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89, 239–250 (1997).
Prodromou, C. et al. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90, 65–75 (1997).
Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nature Rev. Cancer 5, 761–772 (2005).
Meyer, P. et al. Structural and functional analysis of the middle segment of Hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions. Mol. Cell 11, 647–658 (2003).
Cunningham, C. N., Krukenberg, K. A. & Agard, D. A. Intra- and intermonomer interactions are required to synergistically facilitate ATP hydrolysis in Hsp90. J. Biol. Chem. 283, 21170–21178 (2008).
Tsutsumi, S. et al. Hsp90 charged-linker truncation reverses the functional consequences of weakened hydrophobic contacts in the N domain. Nature Struct. Mol. Biol. 16, 1141–1147 (2009).
Sato, S., Fujita, N. & Tsuruo, T. Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl Acad. Sci. USA 97, 10832–10837 (2000).
Harris, S. F., Shiau, A. K. & Agard, D. A. The crystal structure of the carboxy-terminal dimerization domain of htpG, the Escherichia coli Hsp90, reveals a potential substrate binding site. Structure 12, 1087–1097 (2004).
Minami, Y., Kimura, Y., Kawasaki, H., Suzuki, K. & Yahara, I. The carboxy-terminal region of mammalian HSP90 is required for its dimerization and function in vivo. Mol. Cell. Biol. 14, 1459–1464 (1994).
Garnier, C. et al. Binding of ATP to heat shock protein 90: evidence for an ATP-binding site in the C-terminal domain. J. Biol. Chem. 277, 12208–12214 (2002).
Soti, C., Racz, A. & Csermely, P. A nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket. J. Biol. Chem. 277, 7066–7075 (2002).
Young, J. C., Obermann, W. M. & Hartl, F. U. Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90. J. Biol. Chem. 273, 18007–18010 (1998).
Csermely, P. et al. ATP induces a conformational change of the 90-kDa heat shock protein (hsp90). J. Biol. Chem. 268, 1901–1907 (1993).
Grenert, J. P. et al. The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J. Biol. Chem. 272, 23843–23850 (1997).
Sullivan, W. et al. Nucleotides and two functional states of hsp90. J. Biol. Chem. 272, 8007–8012 (1997).
Chadli, A. et al. Dimerization and N-terminal domain proximity underlie the function of the molecular chaperone heat shock protein 90. Proc. Natl Acad. Sci. USA 97, 12524–12529 (2000).
Prodromou, C. et al. The ATPase cycle of Hsp90 drives a molecular 'clamp' via transient dimerization of the N-terminal domains. EMBO J. 19, 4383–4392 (2000).
Maruya, M., Sameshima, M., Nemoto, T. & Yahara, I. Monomer arrangement in HSP90 dimer as determined by decoration with N and C-terminal region specific antibodies. J. Mol. Biol. 285, 903–907 (1999).
Nadeau, K., Sullivan, M. A., Bradley, M., Engman, D. M. & Walsh, C. T. 83-kilodalton heat shock proteins of trypanosomes are potent peptide-stimulated ATPases. Protein Sci. 1, 970–979 (1992).
Southworth, D. R. & Agard, D. A. Species-dependent ensembles of conserved conformational states define the Hsp90 chaperone ATPase cycle. Mol. Cell 32, 631–640 (2008). This study provides important glimpses of dynamic differences and nucleotide-specific conformations of HSP90 from bacteria, yeast and humans by cryo-EM.
Hessling, M., Richter, K. & Buchner, J. Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90. Nature Struct. Mol. Biol. 16, 287–293 (2009).
McLaughlin, S. H. et al. The co-chaperone p23 arrests the Hsp90 ATPase cycle to trap client proteins. J. Mol. Biol. 356, 746–758 (2006).
Phillips, J. J. et al. Conformational dynamics of the molecular chaperone Hsp90 in complexes with a co-chaperone and anticancer drugs. J. Mol. Biol. 372, 1189–1203 (2007).
Graf, C., Stankiewicz, M., Kramer, G. & Mayer, M. P. Spatially and kinetically resolved changes in the conformational dynamics of the Hsp90 chaperone machine. EMBO J. 28, 602–613 (2009).
Johnson, J. L. & Brown, C. Plasticity of the Hsp90 chaperone machine in divergent eukaryotic organisms. Cell Stress Chaperones 14, 83–94 (2009).
Jascur, T. et al. Regulation of p21WAF1/CIP1 stability by WISp39, a Hsp90 binding TPR protein. Mol. Cell 17, 237–249 (2005).
Smith, D. F. et al. Identification of a 60-kilodalton stress-related protein, p60, which interacts with hsp90 and HSP70. Mol. Cell. Biol. 13, 869–876 (1993).
Silverstein, A. M. et al. Protein phosphatase 5 is a major component of glucocorticoid receptor·hsp90 complexes with properties of an FK506-binding immunophilin. J. Biol. Chem. 272, 16224–16230 (1997).
Dolinski, K., Muir, S., Cardenas, M. & Heitman, J. All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 94, 13093–13098 (1997).
Riggs, D. L. et al. Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling. Mol. Cell. Biol. 27, 8658–8669 (2007).
Riggs, D. L. et al. Functional specificity of co-chaperone interactions with Hsp90 client proteins. Crit. Rev. Biochem. Mol. Biol. 39, 279–295 (2004).
Riggs, D. L. et al. The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. EMBO J. 22, 1158–1167 (2003).
Cintron, N. S. & Toft, D. Defining the requirements for Hsp40 and HSP70 in the Hsp90 chaperone pathway. J. Biol. Chem. 281, 26235–26244 (2006).
Siligardi, G. et al. Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc37. J. Biol. Chem. 277, 20151–20159 (2002).
Prodromou, C. et al. Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. EMBO J. 18, 754–762 (1999).
Panaretou, B. et al. Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone Aha1. Mol. Cell 10, 1307–1318 (2002).
McLaughlin, S. H., Smith, H. W. & Jackson, S. E. Stimulation of the weak ATPase activity of human Hsp90 by a client protein. J. Mol. Biol. 315, 787–798 (2002).
Meyer, P. et al. Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. EMBO J. 23, 511–519 (2004).
Retzlaff, M. et al. Asymmetric activation of the Hsp90 dimer by its cochaperone Aha1. Mol. Cell 37, 344–354.
Roe, S. M. et al. The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50cdc37. Cell 116, 87–98 (2004).
Shao, J. et al. Hsp90 regulates p50cdc37 function during the biogenesis of the active conformation of the heme-regulated eIF2α kinase. J. Biol. Chem. 276, 206–214 (2001).
Shao, J., Irwin, A., Hartson, S. D. & Matts, R. L. Functional dissection of cdc37: characterization of domain structure and amino acid residues critical for protein kinase binding. Biochemistry 42, 12577–12588 (2003).
Silverstein, A. M., Grammatikakis, N, Cochran, B. H., Chinkers, M. & Pratt, W. B. p50cdc37 binds directly to the catalytic domain of Raf as well as to a site on Hsp90 that is topologically adjacent to the tetratricopeptide repeat binding site. J. Biol. Chem. 273, 20090–20095 (1998).
Young, J. C. & Hartl, F. U. Polypeptide release by Hsp90 involves ATP hydrolysis and is enhanced by the co-chaperone p23. EMBO J. 19, 5930–5940 (2000).
Freeman, B. C., Felts, S. J., Toft, D. O. & Yamamoto, K. R. The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies. Genes Dev. 14, 422–434 (2000).
Zhang, M. et al. Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes. EMBO J. 27, 2789–2798 (2008).
Kamal, A. et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003). This paper provides a plausible mechanistic explanation of why tumour cells are more sensitive to HSP90 inhibition than normal cells, suggesting that most of the HSP90 in tumour cells is found in activated complexes with co-chaperones that have greater ATPase activity and a higher affinity for small molecule inhibitors. However, the issue remains controversial.
Maroney, A. C. et al. Dihydroquinone ansamycins: toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives. Biochemistry 45, 5678–5685 (2006).
Wang, X. et al. Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127, 803–815 (2006). This striking study shows that partial knock down of the HSP90 co-chaperone AHA1 can partially rescue the folding defect and physiological function of the most common mutant variant of CFTR , the gene underlying cystic fibrosis.
Ogiso, H. et al. Phosphorylation analysis of 90 kDa heat shock protein within the cytosolic arylhydrocarbon receptor complex. Biochemistry 43, 15510–15519 (2004).
Wandinger, S. K., Suhre, M. H., Wegele, H. & Buchner, J. The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90. EMBO J. 25, 367–376 (2006).
Duval, M., Le Boeuf, F., Huot, J. & Gratton, J. P. Src-mediated phosphorylation of Hsp90 in response to vascular endothelial growth factor (VEGF) is required for VEGF receptor-2 signaling to endothelial NO synthase. Mol. Biol. Cell 18, 4659–4668 (2007).
Mollapour, M. et al. Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function. Mol. Cell 37, 333–343 (2010).
Scroggins, B. T. et al. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol. Cell 25, 151–159 (2007).
Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–607 (2005).
Martinez-Ruiz, A. et al. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc. Natl Acad. Sci. USA 102, 8525–8530 (2005).
Xu, W. et al. Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex. Nature Struct. Mol. Biol. 12, 120–126 (2005).
Brugge, J. S., Erikson, E. & Erikson, R. L. The specific interaction of the Rous sarcoma virus transforming protein, pp60src, with two cellular proteins. Cell 25, 363–372 (1981).
Lipsich, L. A., Cutt, J. R. & Brugge, J. S. Association of the transforming proteins of Rous, Fujinami, and Y73 avian sarcoma viruses with the same two cellular proteins. Mol. Cell. Biol. 2, 875–880 (1982).
Joab, I. et al. Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones. Nature 308, 850–853 (1984).
Schuh, S. et al. A 90,000-dalton binding protein common to both steroid receptors and the Rous sarcoma virus transforming protein, pp60v-src. J. Biol. Chem. 260, 14292–14296 (1985).
Sanchez, E. R., Toft, D. O., Schlesinger, M. J. & Pratt, W. B. Evidence that the 90-kDa phosphoprotein associated with the untransformed L-cell glucocorticoid receptor is a murine heat shock protein. J. Biol. Chem. 260, 12398–12401 (1985).
García-Cardeña, G. et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 392, 821–824 (1998).
Holt, S. E. et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev. 13, 817–826 (1999).
Minet, E. et al. Hypoxia-induced activation of HIF-1: role of HIF-1α–Hsp90 interaction. FEBS Lett. 460, 251–256 (1999).
Sato, N. et al. Involvement of heat-shock protein 90 in the interleukin-6-mediated signaling pathway through STAT3. Biochem. Biophys. Res. Commun. 300, 847–852 (2003).
Sepehrnia, B., Paz, I. B., Dasgupta, G. & Momand, J. Heat shock protein 84 forms a complex with mutant p53 protein predominantly within a cytoplasmic compartment of the cell. J. Biol. Chem. 271, 15084–15090 (1996).
Tariq, M., Nussbaumer, U., Chen, Y., Beisel, C. & Paro, R. Trithorax requires Hsp90 for maintenance of active chromatin at sites of gene expression. Proc. Natl Acad. Sci. USA 106, 1157–1162 (2009).
Takahashi, A., Casais, C., Ichimura, K. & Shirasu, K. HSP90 interacts with RAR1 and SGT1 and is essential for RPS2-mediated disease resistance in Arabidopsis. Proc. Natl Acad. Sci. USA 100, 11777–11782 (2003).
Lu, R. et al. High throughput virus-induced gene silencing implicates heat shock protein 90 in plant disease resistance. EMBO J. 22, 5690–5699 (2003). References 111 and 112 show that HSP90 and the co-chaperones SGT1 and RAR1 bind to and stabilize R proteins, which are required for innate immunity in plants. Thus, pharmacological inhibition or genetic knock down of HSP90 reduces plant resistance to several pathogens.
Mayor, A., Martinon, F., De Smedt, T., Petrilli, V. & Tschopp, J. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nature Immunol. 8, 497–503 (2007).
Li, Z., Dai, J., Zheng, H., Liu, B. & Caudill, M. An integrated view of the roles and mechanisms of heat shock protein gp96-peptide complex in eliciting immune response. Front. Biosci. 7, d731–d751 (2002).
Kunisawa, J. & Shastri, N. Hsp90α chaperones large C-terminally extended proteolytic intermediates in the MHC class I antigen processing pathway. Immunity 24, 523–534 (2006).
Zhao, R. et al. Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation. J. Cell Biol. 180, 563–578 (2008).
Boulon, S. et al. The Hsp90 chaperone controls the biogenesis of L7Ae RNPs through conserved machinery. J. Cell Biol. 180, 579–595 (2008).
Suzuki, Y. et al. The Hsp90 inhibitor geldanamycin abrogates colocalization of eIF4E and eIF4E-transporter into stress granules and association of eIF4E with eIF4G. J. Biol. Chem. 284, 35597–35604 (2009).
Tahbaz, N., Carmichael, J. B. & Hobman, T. C. GERp95 belongs to a family of signal-transducing proteins and requires Hsp90 activity for stability and Golgi localization. J. Biol. Chem. 276, 43294–43299 (2001).
Johnston, M., Geoffroy, M. C., Sobala, A., Hay, R. & Hutvagner, G. HSP90 protein stabilizes unloaded Argonaute complexes and microscopic P-bodies in human cells. Mol. Biol. Cell 21, 1462–1469 (2010).
Pare, J. M. et al. Hsp90 regulates the function of argonaute 2 and its recruitment to stress granules and P-bodies. Mol. Biol. Cell 20, 3273–3284 (2009).
Smith, M. R. et al. Cyclophilin 40 is required for microRNA activity in Arabidopsis. Proc. Natl Acad. Sci. USA 106, 5424–5429 (2009).
Specchia, V. et al. Hsp90 prevents phenotypic variation by suppressing the mutagenic activity of transposons. Nature 463, 662–665 (2010).
Breitkreutz, B. J. et al. The BioGRID interaction database: 2008 update. Nucleic Acids Res. 36, D637–D640 (2008).
Kerner, M. J. et al. Proteome-wide analysis of chaperonin-dependent protein folding in Escherichia coli. Cell 122, 209–220 (2005).
Nathan, D. F., Vos, M. H. & Lindquist, S. In vivo functions of the Saccharomyces cerevisiae Hsp90 chaperone. Proc. Natl Acad. Sci. USA 94, 12949–12956 (1997).
Grad, I. & Picard, D. The glucocorticoid responses are shaped by molecular chaperones. Mol. Cell. Endocrinol. 275, 2–12 (2007).
Caplan, A., Mandal, A. & Theodoraki, M. Molecular chaperones and protein kinase quality control. Trends Cell Biol. 17, 87–92 (2007).
Rudiger, S., Buchberger, A. & Bukau, B. Interaction of HSP70 chaperones with substrates. Nature Struct. Biol. 4, 342–349 (1997).
Yam, A. Y. et al. Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies. Nature Struct. Mol. Biol. 15, 1255–1262 (2008).
Li, R. et al. Hsp90 increases LIM kinase activity by promoting its homo-dimerization. FASEB J. 20, 1218–1220 (2006).
Hikri, E., Shpungin, S. & Nir, U. Hsp90 and a tyrosine embedded in the Hsp90 recognition loop are required for the Fer tyrosine kinase activity. Cell Signal 21, 588–596 (2009).
Citri, A. et al. Hsp90 recognizes a common surface on client kinases. J. Biol. Chem. 281, 14361–14369 (2006).
Gould, C. M., Kannan, N., Taylor, S. S. & Newton, A. C. The chaperones Hsp90 and Cdc37 mediate the maturation and stabilization of protein kinase C through a conserved PXXP motif in the C-terminal tail. J. Biol. Chem. 284, 4921–4935 (2009).
Terasawa, K. et al. Cdc37 interacts with the glycine-rich loop of Hsp90 client kinases. Mol. Cell. Biol. 26, 3378–3389 (2006).
Prince, T. & Matts, R. L. Exposure of protein kinase motifs that trigger binding of Hsp90 and Cdc37. Biochem. Biophys. Res. Commun. 338, 1447–1454 (2005).
Citri, A. et al. Hsp90 recognizes a common surface on client kinases (Supplementary data). J. Biol. Chem. 281, 14361–14369 (2006).
Huse, M. & Kuriyan, J. The conformational plasticity of protein kinases. Cell 109, 275–282 (2002).
Xu, Y. & Lindquist, S. L. Heat-shock protein hsp90 governs the activity of pp60v-src kinase. Proc. Natl Acad. Sci. USA 90, 7074–7078 (1993).
Brugge, J. S. Interaction of the Rous sarcoma virus protein pp60src with the cellular proteins pp50 and pp90. Curr. Top. Microbiol. Immunol. 123, 1–22 (1986).
Xu, Y., Singer, M. A. & Lindquist, S. L. Maturation of the tyrosine kinase c-Src as a kinase and as a substrate depends on the molecular chaperone Hsp90. Proc. Natl Acad. Sci. USA 96, 109–114 (1999).
Falsone, S. F., Leptihn, S., Osterauer, A., Haslbeck, M. & Buchner, J. Oncogenic mutations reduce the stability of SRC kinase. J. Mol. Biol. 344, 281–291 (2004).
Zhang, X., Gureasko, J., Shen, K., Cole, P. A. & Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137–1149 (2006).
Wan, P. T. et al. Mechanism of activation of the RAF–ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).
Shimamura, T., Lowell, A. M., Engelman, J. A. & Shapiro, G. I. Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins. Cancer Res. 65, 6401–6408 (2005).
da Rocha Dias, S. et al. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 65, 10686–10691 (2005).
Grbovic, O. M. et al. V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc. Natl Acad. Sci. USA 103, 657–662 (2006).
Kaul, S. et al. Mutations at positions 547–553 of rat glucocorticoid receptors reveal that hsp90 binding requires the presence, but not defined composition, of a seven-amino acid sequence at the amino terminus of the ligand binding domain. J. Biol. Chem. 277, 36223–36232 (2002).
Giannoukos, G., Silverstein, A. M., Pratt, W. B. & Simons, S. S. Jr. The seven amino acids (547–553) of rat glucocorticoid receptor required for steroid and hsp90 binding contain a functionally independent LXXLL motif that is critical for steroid binding. J. Biol. Chem. 274, 36527–36536 (1999).
Xu, M., Dittmar, K. D., Giannoukos, G., Pratt, W. B. & Simons, S. S. Jr. Binding of hsp90 to the glucocorticoid receptor requires a specific 7-amino acid sequence at the amino terminus of the hormone-binding domain. J. Biol. Chem. 273, 13918–13924 (1998).
McClellan, A. J., Scott, M. D. & Frydman, J. Folding and quality control of the VHL tumor suppressor proceed through distinct chaperone pathways. Cell 121, 739–748 (2005).
Connell, P. et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nature Cell Biol. 3, 93–96 (2001).
Murata, S., Minami, Y., Minami, M., Chiba, T. & Tanaka, K. CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep. 2, 1133–1138 (2001).
Xu, W. et al. Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc. Natl Acad. Sci. USA 99, 12847–12852 (2002).
Morishima, Y. et al. CHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins. Hum. Mol. Genet. 17, 3942–3952 (2008).
Li, W. et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS ONE 3, e1487 (2008).
Petroski, M. D. & Deshaies, R. J. Function and regulation of cullin-RING ubiquitin ligases. Nature Rev. Mol. Cell Biol. 6, 9–20 (2005).
Ehrlich, E. S. et al. Regulation of Hsp90 client proteins by a Cullin5–RING E3 ubiquitin ligase. Proc. Natl Acad. Sci. USA 106, 20330–20335 (2009). In this study elucidating the basis for the effects of HSP90 on proteome stability, cullin 5 is shown to be involved in the degradation of HSP90 client proteins through a non-canonical, elongin-independent pathway.
Horwich, A. L., Fenton, W. A., Chapman, E. & Farr, G. W. Two families of chaperonin: physiology and mechanism. Annu. Rev. Cell Dev. Biol. 23, 115–145 (2007).
Genevaux, P., Georgopoulos, C. & Kelley, W. L. The HSP70 chaperone machines of Escherichia coli: a paradigm for the repartition of chaperone functions. Mol. Microbiol. 66, 840–857 (2007).
Nakamoto, H. & Vigh, L. The small heat shock proteins and their clients. Cell. Mol. Life Sci. 64, 294–306 (2007).
Laskey, R. A., Honda, B. M., Mills, A. D. & Finch, J. T. Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature 275, 416–420 (1978).
Besche, H., Haas, W., Gygi, S. & Goldberg, A. Isolation of mammalian 26S proteasomes and p97/VCP complexes using the ubiquitin-like domain from HHR23B reveals novel proteasome-associated proteins. Biochemistry 48, 2538–2549 (2009).
Baker, D., Sohl, J. L. & Agard, D. A. A protein-folding reaction under kinetic control. Nature 356, 263–265 (1992).
Chen, B., Zhong, D. & Monteiro, A. Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms. BMC Genomics 7, 156 (2006).
Pridgeon, J. W., Olzmann, J. A., Chin, L. S. & Li, L. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol. 5, e172 (2007).
Yang, Y. & Li, Z. Roles of heat shock protein gp96 in the ER quality control: redundant or unique function? Mol. Cells 20, 173–182 (2005).
Cowen, L. E. & Lindquist, S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309, 2185–2189 (2005).
Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998).
Queitsch, C., Sangster, T. A. & Lindquist, S. Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–624 (2002).
Yeyati, P. L., Bancewicz, R. M., Maule, J. & van Heyningen, V. Hsp90 selectively modulates phenotype in vertebrate development. PLoS Genet. 3, e43 (2007).
Sangster, T. A. et al. HSP90 affects the expression of genetic variation and developmental stability in quantitative traits. Proc. Natl Acad. Sci. USA 105, 2963–2968 (2008).
Sangster, T. A. et al. HSP90-buffered genetic variation is common in Arabidopsis thaliana. Proc. Natl Acad. Sci. USA 105, 2969–2974 (2008).
Sollars, V. et al. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nature Genet. 33, 70–74 (2003).
Tokuriki, N. & Tawfik, D. S. Chaperonin overexpression promotes genetic variation and enzyme evolution. Nature 459, 668–673 (2009).
Stephanou, A. & Latchman, D. S. Transcriptional regulation of the heat shock protein genes by STAT family transcription factors. Gene Expression 7, 311–319 (1999).
Chen, C. Y. & Balch, W. E. The HSP90 chaperone complex regulates GDI-dependent Rab recycling. Mol. Biol. Cell 17, 3494–3507 (2007).
Lotz, G. P., Brychzy, A., Heinz, S. & Obermann, W. M. A novel HSP90 chaperone complex regulates intercellular vesicle transport. J. Cell Sci. 121, 717–723 (2008)
We thank C. McClellan, L. Pepper and L. Whitesell for helpful comments and suggestions. M.T. is supported by the Human Frontier Science Program long-term fellowship. D.F.J. is a Howard Hughes Medical Institute fellow of the Damon Runyon Cancer Research Foundation (DRG-1964-08). S.L. is an investigator of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
- Macromolecular crowding
The exclusion of the volume available for biochemical reactions in solutions with high concentrations of macromolecules. Crowding promotes intermolecular interactions.
The adoption of an inappropriate conformation or unfolded state and/or aggregation that can occur as a result of macromolecular crowding, environmental stress or mutation.
The homeostasis of a functional protein in the cell, which is a product of its concentration, conformation, interactions, localization and turnover.
A protein that assists in the folding of a protein or assembly of a complex but does not otherwise contribute to the final structure or function of the product.
- Protein remodelling factor
A protein that remodels the structure and conformation of its target macromolecules, often in a manner that requires ATP hydrolysis.
- Ubiquitin–proteasome system
A major mechanism of protein degradation in a cell. The covalent tagging of proteins with another small protein, ubiquitin, targets them for degradation by macromolecular assembly of the proteasome.
- Heat shock protein
(HSP). A protein induced in response to increased temperature, classified according to its size. Many HSPs function as molecular chaperones.
A protein that associates with and promotes the function of chaperones by modulating their chaperoning activity and/or regulating their substrate specificity. The definition of a co-chaperone is somewhat arbitrary, as some co-chaperones have chaperoning activity even when they are not associated with the core chaperones.
- X-ray crystallography
A method for determining the precise arrangement of atoms in a crystal, based on its diffraction pattern in an X-ray beam. This technique can be applied to protein crystals to obtain extremely high-resolution structures.
- Electron microscopy
(EM). A form of microscopy that uses a particle beam of electrons to obtain high magnifications (up to 1,000,000-fold). Although EM generally provides lower resolution than other structural techniques, molecules can usually be visualized under closer to physiological conditions.
- Hydrogen–deuterium (H–D) exchange
A reaction in which hydrogen atoms, typically backbone amides in the context of a protein, exchange with deuterium in a D2O-based buffer. The rate at which this exchange occurs is related to how solution-accessible each position is, and indicates whether a given residue is on the surface of the protein or more buried. Surface hydrogen atoms involved in hydrogen bonding interactions will not exchange.
- Small nuclear RNP
A low molecular weight RNA, associated with proteins. Small nuclear RNPs mediate the splicing of primary RNA transcripts.
A family of proteins that are characterized by the presence of two homology domains: PAZ and PIWI. These proteins are essential for diverse RNA silencing pathways.
- Molten globule
A partially denatured protein conformation with secondary structure similar to the native fold but without a fixed tertiary structure. Many proteins remain in such a state during folding or under partially denaturing conditions.
About this article
Cite this article
Taipale, M., Jarosz, D. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11, 515–528 (2010). https://doi.org/10.1038/nrm2918
Developmental & Comparative Immunology (2021)
Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics
First report of cystic echinococcosis caused by Echinococcus granulosus sensu stricto/G1 in Felis catus from the Patagonian region of Argentina
Parasitology Research (2021)
STIP1 knockdown suppresses colorectal cancer cell proliferation, migration and invasion by inhibiting STAT3 pathway
Chemico-Biological Interactions (2021)
Denatured corona proteins mediate the intracellular bioactivities of nanoparticles via the unfolded protein response